Inhibitors of IMPDH enzyme

ABSTRACT

The present invention relates to compounds which inhibit IMPDH. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH-mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.

TECHNICAL FIELD OF THE INVENTION

[0001] This application claims priority from U.S. ProvisionalApplications Serial No. 60/125,507 Filed Mar. 19, 1999 and U.S.Provisional Serial No. 60/174,882 filed Jan. 7, 2000.

[0002] The present invention relates to compounds which inhibit IMPDH.This invention also relates to pharmaceutical compositions comprisingthese compounds. The compounds and pharmaceutical compositions of thisinvention are particularly well suited for inhibiting IMPDH enzymeactivity and consequently, may be advantageously used as therapeuticagents for IMPDH-mediated processes. This invention also relates tomethods for inhibiting the activity of IMPDH using the compounds of thisinvention and related compounds.

BACKGROUND OF THE INVENTION

[0003] The synthesis of nucleotides in organisms is required for thecells in those organisms to divide and replicate. Nucleotide synthesisin mammals may be achieved through one of two pathways: the de novosynthesis pathway or the salvage pathway. Different cell types use thesepathways to a different extent.

[0004] Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) isan enzyme involved in the de novo synthesis of guanine nucleotides.IMPDH catalyzes the NAD-dependent oxidation of inosine-5′-monophosphate(IMP) to xanthosine-5′-monophosphate (XMP) [Jackson R. C. et. al.,Nature, 256, pp. 331-333, (1975)].

[0005] IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y.Natsumeda & S. F. Carr, Ann. N.Y. Acad., 696, pp. 88-93 (1993)]. Theprokaryotic forms share 30-40% sequence identity with the human enzyme.Two isoforms of human IMPDH, designated type I and type II, have beenidentified and sequenced [F. R. Collart and E. Huberman, J. Biol. Chem.,263, pp. 15769-15772, (1988); Y. Natsumeda et. al., J. Biol. Chem., 265,pp. 5292-5295, (1990)]. Each is 514 amino acids, and they share 84%sequence identity. Both IMPDH type I and type II form active tetramersin solution, with subunit molecular weights of 56 kDa [Y. Yamada et.al., Biochemistry, 27, pp. 2737-2745 (1988)].

[0006] The de novo synthesis of guanosine nucleotides, and thus theactivity of IMPDH, is particularly important in B and T-lymphocytes.These cells depend on the de novo, rather than salvage pathway togenerate sufficient levels of nucleotides necessary to initiate aproliferative response to mitogen or antigen [A. C. Allison et. al.,Lancet II, 1179, (1975) and A. C. Allison et. al., Ciba Found. Symp.,48, 207, (1977)]. Thus, IMPDH is an attractive target for selectivelyinhibiting the immune system without also inhibiting the proliferationof other cells.

[0007] Immunosuppression has been achieved by inhibiting a variety ofenzymes including for example, the phosphatase calcineurin (inhibited bycyclosporin and FK-506); dihydroorotate dehydrogenase, an enzymeinvolved in the biosynthesis of pyrimidines (inhibited by leflunomideand brequinar); the kinase FRAP (inhibited by rapamycin); and the heatshock protein hsp70 (inhibited by deoxyspergualin). [See B. D. Kahan,Immunological Reviews, 136, pp. 29-49 (1993); R. E. Morris, The Journalof Heart and Lung Transplantation, 12(6), pp. S275-S286 (1993)].

[0008] Inhibitors of IMPDH are also known. U.S. Pat. No. 5,380,879 and5,444,072 and PCT publications WO94/01105 and WO 94/12184 describemycophenolic acid (MPA) and some of its derivatives as potent,uncompetitive, reversible inhibitors of human IMPDH type I (K_(i)=33 nM)and type II (K_(i)=9 nM). MPA has been demonstrated to block theresponse of B and T-cells to mitogen or antigen [A. C. Allison et. al.,Ann. N. Y. Acad. Sci., 696, 63, (1993).

[0009] Immunosuppressants, such as MPA, are useful drugs in thetreatment of transplant rejection and autoimmune diseases. [R. E.Morris, Kidney Intl., 49, Suppl. 53, S-26, (1996)]. However, MPA ischaracterized by undesirable pharmacological properties, such asgastrointestinal toxicity. [L. M. Shaw, et. al., Therapeutic DrugMonitoring, 17, pp. 690-699, (1995)].

[0010] Nucleoside analogs such as tiazofurin, ribavirin and mizoribinealso inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. 849-854(1990)]. These compounds, however, suffer from lack of specificity toIMPDH.

[0011] Mycophenolate mofetil, a prodrug which quickly liberates free MPAin vivo, was recently approved to prevent acute renal allograftrejection following kidney transplantation. [L. M. Shaw, et. al.,Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger,Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations,however, limit the therapeutic potential of this drug. [L. M. Shaw, et.al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)]. MPA israpidly metabolized to the inactive glucuronide in vivo. [A. C. Allisonand E. M. Eugui, Immunological Reviews, 136, pp. 5-28 (1993)]. Theglucuronide then undergoes enterohepatic recycling causing accumulationof MPA in the gastrointestinal tract where it cannot exert its IMPDHinhibitory activity on the immune system. This effectively lowers thedrug's in vivo potency, while increasing its undesirablegastrointestinal side effects.

[0012] More recently, IMPDH inhibitors of different classes have beendescribed in PCT publications WO 97/40028 and WO 98/40381.

[0013] It is also known that IMPDH plays a role in other metabolicevents. Increased IMPDH activity has been observed in rapidlyproliferating human leukemic cell lines and other tumor cell lines,indicating IMPDH as a target for anti-cancer as well asimmunosuppressive chemotherapy [M. Nagai et. al., Cancer Res., 51, pp.3886-3890, (1991)]. IMPDH has also been shown to play a role in theproliferation of smooth muscle cells, indicating that inhibitors ofIMPDH, such as MPA or rapamycin, may be useful in preventing restenosisor other hyperproliferative vascular diseases [C. R. Gregory et al.,Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; andPCT publication WO 94/01105].

[0014] Additionally, IMPDH has been shown to play a role in viralreplication in some virus-infected cell lines. [S. F. Carr, J. Biol.Chem., 268, pp. 27286-27290 (1993)]. Analogous to lymphocytes andlymphocytic and tumor cell lines, the implication is that the de novo,rather than the salvage, pathway is critical in the process of viralreplication.

[0015] Thus, there remains a need for potent IMPDH inhibitors withimproved pharmacological properties. Such inhibitors would havetherapeutic potential as immunosuppressants, anti-cancer agents,anti-vascular hyperproliferative agents, anti-inflammatory agents,antifungal agents, antipsoriatic and anti-viral agents.

SUMMARY OF THE INVENTION

[0016] The present invention provides compounds, and pharmaceuticallyacceptable derivatives thereof, that are useful as inhibitors of IMPDH.The compounds of this invention can be used alone or in combination withother therapeutic or prophylactic agents, such as anti-virals,anti-inflammatory agents, antibiotics, and immunosuppressants for thetreatment or prophylaxis of transplant rejection and autoimmune disease.

[0017] Additionally, these compounds are useful, alone or in combinationwith other agents, as therapeutic and prophylactic agents for antiviral,anti-tumor, anti-cancer, anti-inflammatory agents, antifungal agents,antipsoriatic immunosuppressive chemotherapy and restenosis therapyregimens.

[0018] The invention also provides pharmaceutical compositionscomprising the compounds of this invention, as well as multi-componentcompositions comprising additional IMPDH compounds together with animmunosuppressant. The invention also provides methods of using thecompounds of this invention, as well as other related compounds, for theinhibition of IMPDH.

DETAILED DESCRIPTION OF THE INVENTION

[0019] In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. In thedescription, the following abbreviations are used: Designation Reagentor Fragment Ac acetyl Me methyl Et ethyl Bn benzyl CDIcarbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIEAdiisopropylethylamine DMAP dimethylaminopyridine DMF dimethylformamideDMSO dimethylsulfoxide DPPA diphenyl phosphoryl acid EDC1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAc ethylacetate IPA isopropyl alcohol MeCN acetonitrile THF tetrahydrofuran TEAtriethylamine t-bu tert-butyl BOC butyloxycarbonyl

[0020] The following terms are employed herein:

[0021] Unless expressly stated to the contrary, the terms “—SO₂—” and“—S(O)₂—” as used herein refer to a sulfone or sulfone derivative (i.e.,both appended groups linked to the S), and not a sulfinate ester.

[0022] The terms “halo” or “halogen” refer to a radical of fluorine,chlorine, bromine or iodine.

[0023] The term “immunosuppressant” refers to a compound or drug whichpossesses immune response inhibitory activity. Examples of such agentsinclude cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin,prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferonand mizoribine.

[0024] The term “interferon” refers to all forms of interferons,including but not limited to alpha, beta and gamma forms.

[0025] IMPDH-mediated disease refers to any disease state in which theIMPDH enzyme plays a regulatory role in the metabolic pathway of thatdisease. Examples of IMPDH-mediated disease include transplant rejectionand autoimmune diseases, such as rheumatoid arthritis, multiplesclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, aswell as inflammatory diseases, cancer, viral replication diseases andvascular diseases.

[0026] For example, the compounds, compositions and methods of usingthem of this invention may be used in the treatment of transplantrejection (e.g., kidney, liver, heart, lung, pancreas (islet cells),bone marrow, cornea, small bowel and skin allografts and heart valvexenografts), rheumatoid arthritis, multiple sclerosis, juvenilediabetes, asthma, inflammatory bowel disease (Crohn's disease,ulcerative colitis), lupus, diabetes mellitus, myasthenia gravis,psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eyeuveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, Behcet'sor Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolyticanaemia, idiopathic adrenal insufficiency, polyglandular autoimmunesyndrome, and glomerulonephritis, scleroderma, lichen planus, viteligo(depigmentation of the skin), autoimmune thyroiditis, and alveolitis,inflammatory diseases such as osteoarthritis, acute pancreatitis,chronic pancreatitis, asthma and adult respiratory distress syndrome, aswell as in the treatment of cancer and tumors, such as solid tumors,lymphomas and leukemia, vascular diseases, such as restenosis, stenosisand atherosclerosis, and DNA and RNA viral replication diseases, such asretroviral diseases, and herpes.

[0027] Additionally, IMPDH enzymes are also known to be present inbacteria and thus may regulate bacterial growth. As such, theIMPDH-inhibitor compounds, compositions and methods described herein maybe useful in treatment or prevention of bacterial infection, alone or incombination with other antibiotic agents.

[0028] The term “treating” as used herein refers to the alleviation ofsymptoms of a particular disorder in a patient or the improvement of anascertainable measurement associated with a particular disorder. As usedherein, the term “patient” refers to a mammal, including a human.

[0029] The terms “HBV”, “HCV” and “HGV” refer to hepatitis-B virus,hepatitis-C virus and hepatitis-G virus, respectively.

[0030] According to one embodiment, the invention provides compounds offormula A:

[0031] each of R₁ and R₂ is independently selected from hydrogen; —CF₃;—(C₁-C₆)-straight or branched alkyl; —(C₂-C₆)-straight or branchedalkenyl or alkynyl; —(C₁-C₆)-straight or branched alkyl-R₇;—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇ or —R₇; andwherein at least one of R₁ or R₂ is —(C₁-C₆)-straight or branchedalkyl-R₇; —[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇ or —R₇

[0032] wherein up to 4 hydrogen atoms in any of said alkyl, alkenyl oralkynyl are optionally and independently replaced by R₃; or

[0033] wherein R₁ and R₂ are alternatively taken together to formtetrahydrofuranyl, wherein when R₉ is hydrogen, (R)-methyl, (R)-ethyl or(R)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is replacedby —OR₆ or —R₇, and wherein when R₉ is (S)-methyl, (S)-ethyl or(S)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran isoptionally replaced by —OR₆ or —R₇;

[0034] wherein when R₉ is hydrogen, (R)-methyl, (R)-ethyl or(R)-hydroxymethyl and each of R₁ and R₂ are independently hydrogen,unsubstituted —(C₁-C₆)-straight or branched alkyl, or unsubstituted—(C₂-C₆)-straight or branched alkenyl or alkynyl, then the portion ofthe compound represented by —CH(R₁)R₂ is a C₅-C₁₂ straight or branchedalkyl, alkenyl or alkynyl;

[0035] each R₃ is independently selected from halo, CN, —OR₄, or—N(R₅)₂;

[0036] R₄ is selected from hydrogen, —(C₁-C₆)-straight or branchedalkyl, —(C₂-C₆)-straight or branched alkenyl or alkynyl,—[(C₁-C₆)-straight or branched alkyl]-R₇, —[(C₂-C₆)-straight or branchedalkenyl or alkynyl]-R₇, —C(O)—[(C₁-C₆)-straight or branched alkyl],—C(O)—[(C₂-C₆)-straight or branched alkenyl or alkynyl],—C(O)—[(C₁-C₆)-straight or branched alkyl]-N(R₈)₂,—C(O)—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-N(R₈)₂,—P(O)(OR₈)₂, —P(O)(OR₈)(R₈), —C(O)—R₇, —[(C₁-C₆)-straight or branchedalkyl]-CN, —S(O)₂N(R₅)₂ or —[(C₂-C₆)-straight or branched alkenyl oralkynyl]-CN;

[0037] each R₅ is independently selected from hydrogen,—(C₁-C₆)-straight or branched alkyl, —(C₂-C₆)-straight or branchedalkenyl or alkynyl, —[(C₁-C₆)-straight or branched alkyl]-R₇,—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇,—[(C₁-C₆)-straight alkyl]-CN, —[(C₂-C₆)-straight or branched alkenyl oralkynyl]-CN, —[(C₁-C₆)-straight or branched alkyl]-OR₄,—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₄,—C(O)—(C₁-C₆)-straight or branched alkyl, —C(O)—[(C₂-C₆)-straight orbranched alkenyl or alkynyl], —C(O)—R₇, —C(O)O—R₇,—C(O)O—(C₁-C₆)-straight or branched alkyl, —C(O)O—[(C₂-C₆)-straight orbranched alkenyl or alkynyl], —S(O)₂—(C₁-C₆)-straight or branched alkyl,or —S(O)₂—R₇; or two R₅ moieties, when bound to the same nitrogen atom,are taken together with said nitrogen atom to form a 3 to 7-memberedheterocyclic ring, wherein said heterocyclic ring optionally contains 1to 3 additional heteroatoms independently selected from N, O, S, S(O) orS(O)₂;

[0038] R₆ is selected from —C(O)—CH₃, —CH₂—C(O)—OH, —CH₂—C(O)—(O)—tBu,—CH₂—CN, or —CH₂—C≡CH;

[0039] each R₇ is a monocyclic or bicyclic ring system wherein in saidring system:

[0040] i. each ring comprises 3 to 7 ring atoms independently selectedfrom C, N, O or S;

[0041] ii. no more than 4 ring atoms are selected from N, O or S;

[0042] iii. any CH₂ is optionally replaced with C(O);

[0043] iv. any S is optionally replaced with S(O) or S(O)₂;

[0044] each R₈ is independently selected from hydrogen or—[C₁-C₄]-straight or branched alkyl;

[0045] wherein in any ring system in said compound up to 3 hydrogenatoms bound to the ring atoms are optionally and independently replacedwith halo, hydroxy, nitro, cyano, amino, (C₁-C₄)-straight or branchedalkyl; O—(C₁-C₄)-straight or branched alkyl, (C₂-C₄)-straight orbranched alkenyl or alkynyl, or O—(C₂-C₄)-straight or branched alkenylor alkynyl; and

[0046] wherein any ring system is optionally benzofused;

[0047] R₉ is selected from hydrogen, (R)-methyl, (S)-methyl, (R)-ethyl,(S)-ethyl, (R)-hydroxymethyl or (S)-hydroxymethyl;

[0048] R₁₀ is selected from —C═N or 5-oxazolyl; and

[0049] R₁₁ is selected from halo, —O—(C₁-C₃) straight alkyl, or—O—(C₂-C₃) straight alkenyl or alkynyl.

[0050] Also within the scope of formula (A) are prodrugs, which areformed by esterifying either or both of R₁ or R₂. Examples of suchprodrugs are compounds 143 to 156 in Table 1, set forth below.

[0051] The term “monocyclic ring system”, as used herein, includessaturated, partially unsaturated and fully unsaturated ring structures.The term “bicyclic ring system”, as used herein, includes systemswherein each ring is independently saturated, partially unsaturated andfully unsaturated. Examples of monocyclic and bicyclic ring systemsuseful in the compounds of this invention include, but are not limitedto, cyclopentane, cyclopentene, indane, indene, cyclohexane,cyclohexene, cyclohexadiene, benzene, tetrahydronaphthalene,decahydronaphthalene, naphthalene, pyridine, piperidine, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,1,2,3,4-tetrazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrahydroquinoline,quinoline, 1,2,3,4-tetrahydroisoquinoline, isoquinoline, cinnoline,phthalazine, quinazoline, quinoxaline, 1,5-naphthyridine,1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine,2,6-naphthyridine, 2,7-naphthyridine, pteridine, acridine, phenazine,1,10-phenatroline, dibenzopyrans, 1-benzopyrans, phenothiazine,phenoxazine, thianthrene, dibenzo-p-dioxin, phenoxathiin,phenoxthionine, morpholine, thiomorpholine, tetrahydropyan, pyran,benzopyran, 1,4-dioxane, 1,3-dioxane, dihyropyridine, dihydropyran,1-pyrindine, quinuclidine, triazolopyridine, β-carboline, indolizine,quinolizidine, tetrahydronaphtheridine, diazaphenanthrenes, thiopyran,tetrahydrothiopyran, benzodioxane, furan, benzofuran, tetrahydrofuran,pyrrole, indole, thiophene, benzothiopene, carbazole, pyrrolidine,pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole,1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4 oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5 thiadiazole, tetrazole,benzothiazole, benzoxazole, benzotriazole, benzimidazole, benzopyrazole,benzisothiazole, benzisoxazole and purine.

[0052] Additional monocyclic and bicyclic structures falling within theabove description may be found in A. R. Katritzky, and C. W. Rees, eds.“Comprehensive Heterocyclic Chemistry: Structure, Reactions, Synthesisand Use of Heterocyclic Compounds, Vol. 1-8,” Pergamon Press, NY (1984),the disclosure of which is herein incorporated by reference.

[0053] It should be understood that heterocycles may be attached to therest of the compound by any atom of the heterocycle which results in thecreation of a stable structure.

[0054] The term “ring atom”, as used herein, refers to a backbone atomthat makes up the ring. Such ring atoms are selected from C, N, O or Sand are bound to 2 or 3 other such ring atoms (3 in the case of certainring atoms in a bicyclic ring system). The term “ring atom” does notinclude hydrogen.

[0055] The terms “—[(C₁-C₆)-straight or branched alkyl]-X” and“—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-X”, wherein X isanything indicated as being bound to the alkyl, alkenyl or alkynyl,denotes that one or more X groups may be attached to the alkyl, alkenylor alkynyl chain at any termini.

[0056] According to one preferred embodiment, the compound has theformula (I):

[0057] R₁ and R₂ are as defined above, or formula (IA):

[0058] R₉ is selected from (R)-methyl, (S)-methyl, (R)-ethyl, (S)-ethyl,(R)-hydroxymethyl or (S)-hydroxymethyl; and

[0059] R₁, R₂, R₁₀ and R₁₁ are as defined above.

[0060] According to a more preferred embodiment of formula IA, R₉ isselected from (S)-methyl, (S)-ethyl, or (S)-hydroxymethyl methyl. Mostpreferably, R₉ is (S)-methyl. Compounds wherein R₉ is selected from(S)-methyl, (S)-ethyl, or (S)-hydroxymethyl methyl and wherein theportion of the compound represented by —CH(R₁)R₂ is a C₁-C₄ straight orbranched alkyl, or a C₂-C₄ straight or branched alkenyl or alkynyl fallwithin the genus of compounds described in WO 97/40028. However,applicants have discovered that the presence of an (S) oriented moietyat R₉ imparts surprising and unexpectedly increased IMPDH inhibitoryactivity.

[0061] According to another preferred embodiment of formula IA, R₁₁ isselected from O-methyl, O-ethyl or O-isopropyl.

[0062] According to a more preferred embodiment of formulae (I) and(IA), at least one of R₁ or R₂ is selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, phenyl, pyridyl,—CH₂OCH₃, —CH₂CN, —CH₂OCH₂CH₂CN, —CH₂C(CH₃)₂CH₂CH₂CN,—CH₂C(CH₂CH₃)₂CH₂CH₂CN, —CH₂CH₂CN, —CH₂N(CH₂CH₂CN)₂, —CH₂N(CH₃)CH₂CH₂CN,—CH(NH₂)CH₂CN, —CH₂Cl, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,—CH₂CH₂OC(O)CH₃, —CH₂CH₂OC(O)CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂,—CH₂CH₂N(CH₂CH₃)₂, —CH₂N(CH₂CH₃)₂, —CH₂CH₂CH₂N (CH₃)₂,—CH₂CH₂CH₂N⁺(CH₃)₃, —CH₂OCH₂CH(CH₃)₂, —CH₂CH₂N(CH₃)C(O)OC(CH₃)₃,—CH₂N(CH₂CH₂CN)CH₂CH(CH₃)₂, —CH(CH₂CN)N(CH₃)₂,—CH₂CH(CH₂CN)NHC(O)OC(CH₃)₃,

[0063] wherein n is 0 or 1.

[0064] According to an even more preferred embodiment of formula IA, oneof R₁ or R₂ is selected from hydrogen, ethyl or phenyl; and the other ofR₁ or R₂ is selected from —CH₂OH, —CH₂CN, —CH₂CH₂CN or CH₂N(CH₂CH₃)₂; orR₁ and R₂ are taken together to form a 3-tetrahydrofuranyl moiety.

[0065] According to an alternate preferred embodiment of formula I, R₁and R₂ are taken together to form a 3-tetrahydrofuranyl moiety that issubstituted by —OR₆.

[0066] According to another preferred embodiment, the compound offormula A is selected from any of those set forth in Table 1, below.TABLE 1 Compounds. 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

[0067] In the above table, certain compounds are shown as salts. Itshould be understood that the scope of the compounds set forth in anygiven entry in the table covers all forms of the depicted compound, notjust the salt shown.

[0068] When stereochemistry is not specifically indicated, the compoundsof this invention may contain one or more asymmetric carbon atoms andthus may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention, unless otherwise indicated. Each stereogenic carbon may be ofthe R or S configuration.

[0069] Combinations of substituents and variables envisioned by thisinvention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds thatpossess stability sufficient to allow manufacture and maintenance of theintegrity for a sufficient period of time to be useful for the purposesdetailed herein (e.g., therapeutic or prophylactic administration to amammal or for use in affinity chromatography applications). Typically,such compounds are stable at a temperature of 40° C. or less, in theabsence of moisture or other chemically reactive conditions, for atleast a week.

[0070] As used herein, the compounds of this invention, are defined toinclude pharmaceutically acceptable derivatives or prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing (directly or indirectly) a compoundof this invention. Particularly favored derivatives and prodrugs arethose which increase the bioavailability of the compounds of thisinvention when such compounds are administered to a mammal (e.g., byallowing an orally administered compound to be more readily absorbedinto the blood) or which enhance delivery of the parent compound to abiological compartment (e.g., the brain or lymphatic system) relative tothe parent species. Preferred prodrugs include derivatives where a groupwhich enhances aqueous solubility or active transport through the gutmembrane is appended to the structure of the compounds of thisinvention.

[0071] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate. Base saltsinclude ammonium salts, alkali metal salts, such as sodium and potassiumsalts, alkaline earth metal salts, such as calcium and magnesium salts,salts with organic bases, such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, and so forth.

[0072] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates, such asdimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides, such as benzyl and phenethyl bromides and others. Wateror oil-soluble or dispersible products are thereby obtained.

[0073] The compounds of this invention may be synthesized usingconventional techniques. Advantageously, these compounds areconveniently synthesized from readily available starting materials. Morespecifically, the compounds of this invention may be synthesized by theschemes set forth in Examples 1 and 2 with modifications that will bereadily apparent to those of skill in the art.

[0074] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[0075] The novel compounds of the present invention are excellentligands for IMPDH. Accordingly, these compounds are capable of targetingand inhibiting IMPDH enzyme. Inhibition can be measured by variousmethods, including, for example, IMP dehydrogenase HPLC assays(measuring enzymatic production of XMP and NADH from IMP and NAD) andIMP dehydrogenase spectrophotometric assays (measuring enzymaticproduction of NADH from NAD). [See C. Montero et al., Clinica ChimicaActa, 238, pp. 169-178 (1995)].

[0076] Compositions of this invention comprise a compound of thisinvention or a salt thereof; an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,anti-inflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation compound; and any pharmaceuticallyacceptable carrier, adjuvant or vehicle. Alternate compositions of thisinvention comprise a compound of this invention or a salt thereof; and apharmaceutically acceptable carrier, adjuvant or vehicle. Suchcomposition may optionally comprise an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,anti-inflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation compound. Preferably, the compositionsof this invention are pharmaceutical compositions.

[0077] The term “pharmaceutically acceptable carrier or adjuvant” refersto a carrier or adjuvant that may be administered to a patient, togetherwith a compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

[0078] Pharmaceutically acceptable carriers, adjuvants and vehicles thatmay be used in the pharmaceutical compositions of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (SEDDS) suchas dα-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of this invention.

[0079] The pharmaceutical compositions of this invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir. Weprefer oral administration or administration by injection. Thepharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

[0080] The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as those described in Pharmacopeia Helvetica, Ph.Helv., or a similar alcohol, or carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms such as emulsions and orsuspensions Other commonly used surfactants such as Tweens or Spansand/or other similar emulsifying agents or bioavailability enhancerswhich are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

[0081] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carriersthat are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried cornstarch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase and combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

[0082] The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

[0083] Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

[0084] The pharmaceutical compositions of this invention may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

[0085] Dosage levels of between about 0.01 and about 100 mg/kg bodyweight per day, preferably between about 0.5 and about 75 mg/kg bodyweight per day of the IMPDH inhibitory compounds described herein areuseful in a monotherapy and/or in combination therapy for the preventionand treatment of IMPDH-mediated disease. Typically, the pharmaceuticalcompositions of this invention will be administered from about 1 toabout 5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

[0086] When the compositions of this invention comprise a combination ofan IMPDH inhibitor of this invention and one or more additionaltherapeutic or prophylactic agents, both the IMPDH inhibitor and theadditional agent should be present at dosage levels of between about 10to 100%, and more preferably between about 10 to 80% of the dosagenormally administered in a monotherapy regimen. The additional agentsmay be administered separately, as part of a multiple dose regimen, fromthe compounds of this invention. Alternatively, those agents may be partof a single dosage form, mixed together with the compounds of thisinvention in a single composition.

[0087] According to one embodiment, the pharmaceutical compositions ofthis invention comprise an additional immunosuppression agent. Examplesof additional immunosuppression agents include, but are not limited to,cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin,prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferonand mizoribine.

[0088] According to an alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise an anti-canceragent. Examples of anti-cancer agents include, but are not limited to,cisplatin, actinomycin D, doxorubicin, vincristine, vinblastine,etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine,cyclosporin A, phenothiazines, interferon and thioxantheres.

[0089] According to another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise an anti-viralagent. Examples of anti-viral agents include, but are not limited to,Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI,AZT, and acyclovir.

[0090] According to yet another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise ananti-vascular hyperproliferative agent. Examples of anti-vascularhyperproliferative agents include, but are not limited to, HMG Co-Areductase inhibitors such as lovastatin, thromboxane A2 synthetaseinhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors,low molecular weight heparin, mycophenolic acid, rapamycin and5-(3′-pyridinylmethyl)benzofuran-2-carboxylate.

[0091] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

[0092] As the skilled artisan will appreciate, lower or higher dosesthan those recited above may be required. Specific dosage and treatmentregimens for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health status, sex, diet, time ofadministration, rate of excretion, drug combination, the severity andcourse of the disease, the patient's disposition to the disease and thejudgment of the treating physician.

[0093] In an alternate embodiment, this invention provides methods oftreating or preventing IMPDH-mediated disease in a mammal comprising thestep of administrating to said mammal any of the pharmaceuticalcompositions and combinations described above. If the pharmaceuticalcomposition only comprises the IMPDH inhibitor of this invention as theactive component, such methods may additionally comprise the step ofadministering to said mammal an agent selected from an anti-inflammatoryagent, immunosuppressant, an anti-cancer agent, an anti-viral agent, oran anti-vascular hyperproliferation compound. Such additional agent maybe administered to the mammal prior to, concurrently with, or followingthe administration of the IMPDH inhibitor composition.

[0094] In a preferred embodiment, these methods are useful insuppressing an immune response in a mammal. Such methods are useful intreating or preventing diseases, including, transplant rejection (e.g.,kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea,small bowel and skin allografts and heart valve xenografts), graftversus host disease, and autoimmune diseases, such as rheumatoidarthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatorybowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes,mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea,pulmonary inflammation, eye uveitis, Grave's disease, Hashimoto'sthyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), perniciousor immunohaemolytic anaemia, idiopathic adrenal insufficiency,polyglandular autoimmune syndrome, glomerulonephritis, scleroderma,lichen planus, viteligo (depigmentation of the skin), autoimmunethyroiditis, and alveolitis.

[0095] These methods comprise the step of administering to the mammal acomposition comprising a compound of this invention and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional immunosuppressant and apharmaceutically acceptable adjuvant.

[0096] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of this invention; anadditional immunosuppressive agent and a pharmaceutically acceptableadjuvant.

[0097] In an alternate preferred embodiment, these methods are usefulfor inhibiting viral replication in a mammal. Such methods are useful intreating or preventing DNA and RNA viral diseases caused by infectionfor example, by orthomyxoviruses (influenza viruses types A and B),paramyxoviruses (respiratory syncytial virus (RSV), subacute sclerosingpanencephalitis (SSPE) virus) measles and parainfluenza type 3),herpesviruses (HSV-1, HSV-2, HHV-6, HHV-7, HHV-8, Epstein Barr Virus(EBV), cytomegalovirus (HCMV) and varicella zoster virus (VZV)),retroviruses (HIV-1, HIV-2, HTLV-1, HTLV-2), flavi- and pestiviruses(yellow fever virus (YFV), hepatitis C virus (HCV), dengue fever virus,bovine viral diarrhea virus (BVDV), hepatotrophic viruses (hepatitis Avirus (HAV), hepatitis B virus (HBV), hepatitis D virus (HDV), hepatitisE virus (HEV), hepatitis G virus (HGV), Crimean-Congo hemorrhagic fevervirus (CCHF), bunyaviruses (Punta Toro virus, Rift Valley fever virus(RVFV), and sandfly fever Sicilian virus), Hantaan virus, Caraparuvirus), human papilloma viruses, encephalitis viruses (La Crosse virus),arena viruses (Junin and Tacaribe virus), reovirus, vesicular stomatitisvirus, rhinoviruses, enteroviruses (polio virus, coxsackie viruses,encephalomyocarditis virus (EMC)), Lassa fever virus, and togaviruses(Sindbis and Semlike forest viruses) and poxviruses (vaccinia virus),adenoviruses, rubiola, and rubella.

[0098] These methods comprise the step of administering to the mammal acomposition comprising a compound of this invention, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-viral agent and apharmaceutically acceptable adjuvant.

[0099] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of this invention; anadditional anti-viral agent and a pharmaceutically acceptable adjuvant.

[0100] In another alternate preferred embodiment, these methods areuseful for inhibiting vascular cellular hyperproliferation in a mammal.Such methods are useful in treating or preventing diseases, including,restenosis, stenosis, artherosclerosis and other hyperproliferativevascular disease.

[0101] These methods comprise the step of administering to the mammal acomposition comprising a compound of this invention, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-vascularhyperproliferative agent and a pharmaceutically acceptable adjuvant.

[0102] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of this invention; anadditional anti-vascular hyperproliferative agent and a pharmaceuticallyacceptable adjuvant.

[0103] In another alternate preferred embodiment, these methods areuseful for inhibiting tumors and cancer in a mammal. Such methods areuseful in treating or preventing diseases, including, tumors andmalignancies, such as lymphoma, leukemia and other forms of cancer.

[0104] These methods comprise the step of administering to the mammal acomposition comprising a compound of this invention, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-tumor or anti-canceragent and a pharmaceutically acceptable adjuvant.

[0105] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of this invention; anadditional anti-tumor or anti-cancer agent and a pharmaceuticallyacceptable adjuvant.

[0106] In another alternate preferred embodiment, these methods areuseful for inhibiting inflammation and inflammatory diseases in amammal. Such methods are useful in treating or preventing diseases,including, osteoarthritis, acute pancreatitis, chronic pancreatitis,asthma and adult respiratory distress syndrome.

[0107] These methods comprise the step of administering to the mammal acomposition comprising a compound of this invention, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an anti-inflammatory agent and apharmaceutically acceptable adjuvant.

[0108] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLE 1 Synthesis of Compound 41

[0109] A. Synthesis of C4

[0110] To a solution of glacial acetic acid (46 mL), acetic anhydride(46 mL, 485 mmole) and 2-methyl-5-nitroanisole (10.0 g, 60 mmole) at 0°C. was added conc. H₂SO₄ (6.9 mL) in a dropwise fashion. Upon completeaddition, CrO₃ (8.08 g, 80.8 mmole) was added portion-wise over 60 mins.Following an additional 15 mins of stirring at 0° C., the reactionmixture was poured over ice and the resulting precipitate was isolatedby filtration, rinsing with cold H₂O. Purification by flashchromatography, eluting with a gradient of 15-50% EtOAc in hexanes,provided 8.14 g (24%, 51% based on recovered starting material) C1 as awhite solid. The ¹H NMR was consistent with that of the desiredstructure.

[0111] A stirred suspension of C1 (81.94 g, 307 mmole) in dioxane (100mL) was treated with concentrated HCl (20 mL) and heated at refluxovernight. Upon cooling to ambient temperature, the product C2precipitated as a light yellow crystalline solid in a yield of 40.65 g(73.1%). The filtrate was concentrated to a volume of ca. 80 mL and asecond crop of product crystals was driven from solution by the additionof hexanes, yielding 8.91 g (16.0%). Both batches were identical by ¹HNMR and TLC analysis and were consistent with that of the desiredmaterial. The total yield of C2 was 49.56 g (89.1%).

[0112] A solution of C2 (456 mg, 2.51 mmole), tosylmethyl isocyanide(490 mg, 2.51 mmole) and K₂CO₃ (347 mg, 251 mmole) were dissolved inmethanol and heated to reflux for 1.5 hours. The product mixture wasthen concentrated in vacuo, redissolved in CH₂Cl₂, washed with water andbrine, dried over Na₂SO₄ and again concentrated in vacuo. Purifiedproduct C3 was obtained through recrystallization (Et₂O/hexanes) toyield 375 mg (68%). The ¹H NMR was consistent with that of the desiredstructure.

[0113] A solution of C3 (4.214 g, 19.1 mmole) in EtOAc (150 mL) wastreated with 10% Pd/C (1.05 g, 25 wt. % of C3) and subjected to 40 psiH₂(g) (Parr Hydrogenation Apparatus) overnight. The reaction mixture wasfiltered and concentrated in vacuo. Pure product C4 was obtained throughflash chromatography, eluting with a gradient of 30-40% EtOAc/hexanes,in a yield of 3.4 g (93%). The ¹H NMR was consistent with that of thedesired structure.

[0114] B. Synthesis of Compound I113

[0115] A solution of 3-aminobenzylamine (826 mg, 6.87 mmole) andtriethylamine (2.39 mL, 17.18 mmole) was treated withdi-t-butyldicarbonate (1.50 g, 6.87 mmole) and the mixture was stirredat ambient temperature for 2 hours. The reaction was then diluted withCH₂Cl₂, washed with NaHCO₃(aq), water and brine, dried (Na₂SO₄) andconcentrated in vacuo. Pure E1 was obtained by flash chromatography,eluting with 25% EtOAc in hexanes in a yield of 200 mg (46%). The ¹H NMRwas consistent with that of the desired structure.

[0116] A solution of C4 (150 mg, 0.789 mmole) and1,1-dicarbonylimidiazole (160 mg, 0.986 mmole) were combined in THF (5mL) and stirred for 6 hours at ambient temperature. The precipitation ofimidazole was noted. To this was then added E1 (351 mg, 1.58 mmole) andN,N-dimethylaminopyridine (97 mg, 0.789 mmole) and the mixture wasrefluxed overnight, resulting in a homogenous solution. Upon cooling toambient temperature, the reaction was diluted with EtOAc (20 mL), washedwith KHSO₄(aq), water, and brine, dried (MgSO₄) and concentrated. PureI113 was obtained through flash chromatography, eluting with a gradientof 20-30-35% acetone in hexanes in a yield of 164 mg (47%). ¹H NMR (500MHz, d₆-DMSO) δ8.90 (s), 8.75 (s), 8.38 (s), 7.60 (d), 7.51 (s),7.3-7.46 (m), 7.21-7.27 (t), 7.05 (dd), 6.87 (d), 4.12 (d), 3.93 (s),1.44 (s). R_(f) 0.21 (5% MeOH/CH₂Cl₂).

[0117] C. Synthesis of Compound I168

[0118] A suspension of I113 (250 mg, 5.76 mmol) in CH₂Cl₂ (1 mL) wastreated in a dropwise fashion at ambient temperature with severalequivalents of trifluoroacetic acid and stirred for 90 min. Theresulting solution was stripped in vacuo and titrated with CH₂Cl₂ andmethanol. Pure product I168 was isolated by filtration in a yield of 258mg (99%). The ¹H NMR was consistent with that of the desired product.

[0119] D. Synthesis of Compound 41

[0120] To a room temperature solution of 1-methoxy-2-propanol (75 mg,832 μmole) in THF (1.0 mL) was added solid 1,1′-carbonyl diimidazole(121 mg, 749 μmole) in one portion. The resulting mixture was stirred atroom temperature overnight, then treated sequentially with TEA (174 μL,1.25 mmole), solid compound I168 (376 mg, 832 μmole), and DMF (1.0 mL).The resulting solution was stirred at room temperature for one day, thendiluted with ethyl acetate, washed sequentially with water and brine,dried over MgSO₄, filtered, and concentrated in vacuo. The crude productwas then purified by flash chromatography (silica gel, 97.5/1.5 CH₂Cl₂).The chromatographed product was then triturated with a 9/1 mixture ofethyl ether/ethyl acetate to give compound 45 (65 mg, 56% yield) as awhite, powdery solid.

[0121] 1H NMR (500 MHz, acetone-d6): 8.34 (s, 1H); 8.21 (s, 1H); 8.12(s, 1H); 7.67 (s, 1H); 7.65 (dd, 1H); 7.50 (d, 1H); 7.47 (d, 1H); 7.43(s, 1H); 7.25 (dd, 1H); 7.10 (dd, 1H); 6.97 (d, 1H); 6.68 (m, 1H); 4.92(m, 1H); 4.32 (d, 2H); 4.01 (s, 3H); 3.43 (dd, 1H); 3.33 (dd, 1H); 3.31(s, 3H); 1.18 (d, 3H).

[0122] Other compounds of this invention may be prepared in a similarmanner substituting the appropriate alcohol for 1-methoxy-2-propanol[i.e., HO—CH(R₁)(R₂)] in step C.

EXAMPLE 2

[0123] Preparation of Compound 169

[0124] A. Preparation of the left hand side coupling intermediate(R₁₀=cyano):

[0125] Copper(I)cyanide (7.2 g, 80.8 mmole) was combined with2-bromo-5-nitroanisole (I) (15 g, 64.6 mmole) in NMP (70 mL) and heatedto 150° C. overnight under an N₂ atmosphere. The mixture was treatedwith Celite, cooled to room temperature, then diluted with EtOAc and 1.0N NaOH and allowed to stir for 15 minutes. The heterogeneous mixture wasfiltered through a pad of Celite with EtOAc, the phases were separated,and the aqueous phase was washed 3 times with EtOAc. The combinedorganics were washed sequentially with 1.0 N NaOH, water, and brine,then dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was dissolved in CH₂Cl₂, filtered through a short pad of silicagel to remove solids and most colored impurities, then concentrated invacuo to give II (10.41 g, 90%) as a brownish-orange solid.

[0126]¹H NMR (500 MHz, CDCl₃): 7.90 (d, 1H); 7.84 (s, 1H); 7.77 (d, 1H);4.07 (s, 3H).

[0127] To a room temperature solution of II (7.2 g, 40.4 mmoles) inEtOAc-EtOH (220-15 mL) was added 10% Pd/C (1.8 g) resulting in aheterogeneous black mixture. The reaction was placed under 1 atmosphere(balloon) of H₂, warmed to 50° C., and stirred overnight. Reaction wascooled to room temperature, the catalyst was removed via filtration, andthe filtrate was concentrated in vacuo to give III (5.56 g, 93%) as acrystalline solid.

[0128]¹H NMR (500 MHz, CDCl₃): 7.29 (d, 1H); 6.22 (d, 1H); 6.17 (s, 1H);4.20 (broad s, 2H); 3.85 (s, 3H).

[0129] To a room temperature, biphasic mixture of phenyl chloroformate(1.6 mL, 12.82 mmoles) in EtOAc (20 mL) and sat. NaHCO₃ (˜1M, 16 mL) wasadded III (950 mg, 6.41 mmoles) as a solution in EtOAc (10 mL) over a 10minute period. The resulting heterogeneous mixture was stirred at roomtemperature for 30 minutes and then the phases were separated. Theorganic phase was washed with brine, dried over Na₂SO₄, filtered througha pad of silica gel with EtOAc, and concentrated in vacuo to give athick oil. The resulting oil was diluted in toluene (30 mL) and treatedwith hexanes (30 mL) resulting in a thick precipitate. This mixture wasstirred for 30 minutes, filtered, solids washed with 1:1toluene:hexanes, then hexanes alone, and dried to constant weight underhigh vacuum to give IV (1.65 g, 96%) as a white powder.

[0130]¹H NMR (500 MHz, dmso-d6); 10.76 (s, 1H); 7.69 (d, 1H); 7.44 (d,1H); 7.40 (d, 1H); 7.26 (m, 3H); 7.15 (d, 1H); 3.85 (s, 3H).

[0131] B. Preparation of the right hand side coupling intermediate(R₉=S-methyl):

[0132] To a room temperature solution of V (200 g, 1.21 moles) in EtOH(2 L) was added NaBH₄ (50.3 g, 1.33 moles) portionwise over 30 minutes,not allowing the internal temperature to rise over 40° C. The reactionwas allowed to stir at room temperature for 4 hours. It was thenquenched with water (˜100 mL), concentrated in vacuo, diluted withEtOAc, washed twice with water, once with sat. NaHCO₃, dried over MgSO₄,filtered, and concentrated in vacuo to give VI (191.7 g, 95%) as ayellowish power.

[0133]¹H NMR (500 MHz, CDCl₃): 8.21 (s, 1H); 8.09 (d, 1H); 7.70 (d, 1H);7.49 (dd, 1H); 5.01 (dd, 1H); 2.45 (s, 1H); 1.52 (d, 3H).

[0134] To a room temperature solution of VI (181 g, 1.08 moles) wasadded DPPA (250 mL, 1.16 moles) at a rate slow enough to keep thereaction temperature under 45° C. Once the addition of DPPA wascomplete, the mixture was treated with DBU (177 mL, 1.18 moles) at arate slow enough to keep the reaction temperature under 45° C. Uponcomplete addition, the reaction was warmed to 60°0 C. and maintained atthat temperature overnight. The resulting biphasic mixture was cooled toroom temperature, washed sequentially with water, then 0.5 M HCl. Theorganic phase was dried over Na₂SO₄, filtered, and concentrated in vacuoto give a yellow-green oil that was not purified further.

[0135]¹H NMR (500 MHz, CDCl₃): 8.21 (s, 1H); 8.18 (d, 1H); 7.68 (d, 1H);7.56 (q, 1H); 4.76 (dd, 1H); 1.59 (d, 3H).

[0136] To a room temperature solution of VII (8.17 g, 42.51 mmoles) inTHF-water (80 mL-10 mL) was added Ph₃P (12.3 g, 46.76 mmoles) as asolution in THF (20 mL) over a 10 minute period. Nitrogen evolution wasimmediate and constant throughout the addition. The reaction was thenheated to 65° C. overnight, then cooled to room temperature. The crudemixture was concentrated in vacuo, diluted with EtOAc, washed withbrine, dried over Na₂SO₄, and filtered. The resulting filtrate wastreated with 1 N HCl/Et₂O at room temperature over a 10 minute periodresulting in precipitate formation. The mixture was stirred at roomtemperature for 15 minutes, then filtered. The solids were washed withEt₂O to give a yellow powder. The crude amine hydrochloride salt wassuspended in brine/EtOAc, and treated with 10 N NaOH (5 mL, 50 mmoles)at room temperature. The resulting mixture was stirred at roomtemperature until all solids were dissolved. The phases were separated,the aqueous phase was washed with EtOAc twice, the combined organicphases were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude amine was diluted in MeOH (50 mL) andadded to a refluxing solution of L-(+)-tartaric acid (5.33 g, 35.33mmoles) in MeOH (450 mL). A precipitate formed immediately and was thendissolved in the MeOH mixture upon refluxing for 15 minutes. Theinternal temperature was lowered to 50° C. and maintained thereovernight. The internal temperature was then lowered to 30° C. andmaintained for another 24 hours followed by another 24 hours at roomtemperature. The resulting crystals (spikes) were filtered, washed withMeOH and Et₂O, and the mother liquor discarded. The resulting crystalswere dissolved in 200 mL of refluxing MeOH, cooled slowly as describedabove, filtered, and washed with MeOH, then Et₂O to give the first cropof VIII (2.21 g, 20%) as a white solid. The mother liquor wasconcentrated in vacuo, solids dissolved in 50 mL of refluxing MeOH,cooled as above, filtered, and washed with MeOH and Et₂O to give asecond crop of VIII (1.50 g, 13%) as a white solid. The optical puritywas determined on the corresponding phenyl carbamate of each crop tobe >97% ee.

[0137] Enantiomeric excesses were determined using a Chiralcel OD column(0.46 cm×25 cm) made by Daicel Chemical Industries and purchased fromChiral Technologies. The mobile phase employed was a 70:30 hexane:IPAmixture in an isocratic run out to 65 minutes at 0.8 ml/min flow rateusing a 3-4 μl injection of a 1-2 mg/ml solution of the phenyl carbamatedissolved in above mentioned hexane:IPA mixture. The desired S-methylenantiomer elutes first at ˜47.2 minutes while the undesired R-methylenatiomer comes off at ˜51.7 minutes while monitoring at 214, 254, 280nm wavelength.

[0138] All samples were run on a Hewlett Packard Series 1050 HPLC with adiode array detector.

[0139] To a heterogeneous suspension of VIII (1.11 g, 3.51 mmoles) inEtOAc (20 mL) and brine (20 mL) was added 10 N NaOH (0.77 mL, 7.72mmoles) at room temperature. The resulting mixture was stirred at roomtemperature until all salts had dissolved. The phases were thenseparated, and the aqueous phase washed with EtOAc. The combined organicphases were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude nitro-benzylamine was diluted in 7MNH₃-MeOH (20 mL), 20% Pd(OH)₂—C added, and placed under 45 psi of H₂ for5 hours. The resulting mixture was filtered to remove the catalyst,concentrated in vacuo, azeotroped once with CH₂Cl₂, then placed underhigh vacuum to give IX (455 mg, 95%) as a waxy white solid.

[0140]¹H NMR (500 MHz, dmso-d6): 6.91 (dd, 1H); 6.56 (s, 1H); 6.50 (d,1H); 6.38 (d, 1H); 4.90 (broad s, 2H); 3.82 (q, 1H); 3.31 (broad s, 2H);1.18 (d, 3H).

[0141] C. Preparation of Compound 169

[0142] To a room temperature solution of 3-(R)-hydroxy pentanitrile (212mg, 2.14 mmoles) was added CDI (521 mg, 3.21 mmoles) in one portion. Theresulting mixture was stirred at room temperature for 1 hour, thentreated with solid silica gel. The heterogeneous mixture was stirredvigorously for 10 minutes, filtered through a short pad of silica gelwith 4:1 EtOAc:IPA, concentrated in vacuo, azeotroped twice with MeCN,then combined with IX (350 mg, 2.57 mmoles) in MeCN (2 mL) and stirredat room temperature for 1 day. The resulting mixture was diluted withEtOAc, washed with water and then brine, dried over Na₂SO₄, filtered,concentrated, and flash chromatographed (silica gel, 1/2→1/3→0/1hexanes/EtOAc→4/1 EtOAc/IPA) to give X (472 mg, 84%) as a clear, thickoil.

[0143]¹H NMR (500 MHz, dmso-d6): 7.73 (d, 1H); 6.94 (dd, 1H); 6.51 (s,1H); 6.47 (d, 1H); 6.38 (d, 1H); 4.98 (broad s, 2H); 4.67 (m, 1H); 4.49(m, 1H); 2.82 (m, 2H); 1.62 (m, 2H); 1.27 (d, 3H); 0.89 (dd, 3H).

[0144] To a room temperature solution of X (470 mg, 1.80 mmoles) inEtOAc (5 mL) was added IV (440 mg, 1.63 mmoles) and TEA (0.23 mL, 1.63mmoles). The resulting mixture was heated to reflux and stirred at thattemperature for 6 hours. The resulting crude mixture was cooled to roomtemperature, diluted with EtOAc, washed with brine/1N HCl, followed bybrine alone, dried over Na₂SO₄, filtered, concentrated in vacuo, andflash chromatographed (silica gel, 1/1→1/2→1/3→1/4→0/1 hexanes/EtOAc→4/1EtOAc/IPA) to give 169 (740 mg, 100%) as a white, foamy solid.

[0145]¹H NMR (500 MHz, dmso-d6): 9.21 (s, 1H); 8.84 (s, 1H); 7.93 (d,1H); 7.59 (d, 1H); 7.51 (s, 1H); 7.41 (s, 1H); 7.29 (d, 1H); 7.23 (dd,1H); 7.01 (d, 1H); 6.92 (d, 1H); 4.69 (m, 1H); 4.63 (m, 1H); 3.89 (s,3H); 2.82 (m, 2H); 2.62 (m, 2H); 1.31 (d, 3H); 0.90 (t, 3H)

EXAMPLE 3 IMPDH Activity Inhibition Assay

[0146] IMP dehydrogenase activity was assayed following an adaptation ofthe method first reported by Magasanik. [B. Magasanik et al., J. Biol.Chem., 226, p. 339 (1957), the disclosure of which is hereinincorporated by reference]. Enzyme activity was measuredspectrophotometrically, by monitoring the increase in absorbance at 340nm due to the formation of NADH (□340 is 6220 M⁻¹ cm⁻¹). The reactionmixture contained 0.1 M potassium phosphate 8.0, 0.5 mM EDTA, 2 mM DTT,200 μM IMP and enzyme (IMPDH human type II) at a concentration of 15 to50 nM. This solution is incubated at 37° C. for 10 minutes. The reactionis started by adding NAD to a final concentration of 200 μM and theinitial rate is measured by following the linear increase in absorbanceat 340 nm for 10 minutes. For reading in a standard spectrophotometer(path length 1 cm) the final volume in the cuvette is 1.0 ml. The assayhas also been adapted to a 96 well microtiter plate format; in this casethe concentrations of all the reagents remain the same and the finalvolume is decreased to 200 μl.

[0147] For the analysis of inhibitors, the compound in question isdissolved in DMSO to a final concentration of 20 mM and added to theinitial assay mixture for preincubation with the enzyme at a finalvolume of 2-5% (v/v). The reaction is started by the addition of NAD,and the initial rates measured as above. K_(i) determinations are madeby measuring the initial velocities in the presence of varying amountsof inhibitor and fitting the data using the tight-binding equations ofHenderson (Henderson, P. J. F. (1972) Biochem. J. 127, 321].

[0148] These results are shown in Table 2. Category “A” indicates aK_(I) of 10 nM or less, category “B” indicates a K_(I) of greater than10 and less than 50 nM, category “C” indicates a K_(I) of 50 nM orgreater, “ND” indicates inhibitory activity was not determined. TABLE 2IMPDH inhibitory activity. Ki Ki Ki Ki Cmpd (nM) Cmpd (nM) Cmpd (nM)Cmpd (nM) 1 A 48 A 95 A 142 B 2 A 49 A 96 B 143 ND 3 A 50 A 97 B 144 ND4 A 51 A 98 B 145 ND 5 A 52 A 99 B 146 ND 6 A 53 A 100 B 147 ND 7 A 54 A101 A 148 ND 8 A 55 A 102 A 149 ND 9 A 56 A 103 C 150 ND 10 A 57 A 104 B151 ND 11 A 58 A 105 A 152 ND 12 A 59 A 106 C 153 ND 13 A 60 A 107 C 154ND 14 A 61 A 108 C 155 ND 15 A 62 A 109 C 156 ND 16 A 63 A 110 C 157 B17 A 64 ND 111 C 158 B 18 A 65 A 112 C 159 A 19 A 66 A 113 C 160 C 20 A67 A 114 C 161 A 21 A 68 A 115 C 162 B 22 A 69 A 116 C 163 B 23 A 70 A117 C 164 B 24 A 71 A 118 C 165 C 25 A 72 A 119 C 166 C 26 A 73 A 120 C167 C 27 A 74 A 121 ND 168 B 28 A 75 A 122 C 169 A 29 A 76 A 123 C 170 A30 A 77 A 124 C 171 C 31 B 78 A 125 C 172 C 32 A 79 A 126 C 172 C 33 A80 A 127 C 173 C 34 A 81 B 128 C 174 C 35 A 82 C 129 C 175 C 36 A 83 B130 C 176 C 37 A 84 B 131 C 177 C 38 A 85 C 132 C 178 C 39 A 86 B 133 B179 C 40 A 87 A 134 B 180 B 41 A 88 A 135 C 181 A 42 A 89 A 136 C 182 C43 A 90 A 137 C 183 B 44 A 91 A 138 A 184 B 45 A 92 A 139 C 185 B 46 A93 B 140 C 186 C 47 A 94 A 141 B 187 B

[0149] Other compounds of this invention will also have IMPDH inhibitoryactivity.

EXAMPLE 4 Cellular Assays

[0150] A. Isolation of peripheral blood mononuclear cells (PBMCs):

[0151] Human venous blood was drawn from normal healthy volunteers usingheparin as an anti-coagulant. PBMCs were isolated from blood bycentrifugation over Eicoll-paque gradient or CPT tubes(Becton-Dickinson) using standard conditions. PBMCs were harvested,washed and re-suspended in complete RPMI, counted and diluted to 1×10⁶cells/mL.

[0152] B. PBMC and splenocyte proliferation assays:

[0153] 5×10⁴ cells (for human PBMC T cells) or 1×10⁵ cells (for humanPBMC B cells) were added per well of a 96-well plate. For T-cell assays,phyto-hemagglutinin (PHA) was added to a final concentration of 10-20μg/mL per well for cell. For B-cell assays, Staphylococcal protein A(SPAS) was added to a final concentration of 2 μg/mL per well.

[0154] Serial 4-fold dilutions of inhibitor stocks were made in completeRPMI and added to cells such that the final concentration of compoundsranged from 20 μM to 20 nM, while DMSO was maintained at a finalconcentration of 0.1%. The cells were then incubated for 3 days. Allsamples were tested in triplicate. Tritiated thymidine (0.4 μCi/well)was added for the last 24 hours of the assay. The cells were harvestedonto Betaplate filters and counted in a scintillation counter.Concentrations of compounds required to inhibit proliferation of cellsby 50% (IC50 values) were calculated using the SoftMax Pro™ (MolecularDevices) computer software package.

[0155] The results of these assays are shown in Table 3. Category “A”indicates a IC₅₀ of 100 nM or less, category “B” indicates a IC₅₀ ofgreater than 100 and less 1000 nM, category “C” indicates a IC₅₀ of 1000nM or greater, “ND” indicates inhibitory activity was not determined inthe indicated cellular assay. TABLE 3 Cellular Activity T-cells B-cellsT-cells B-cells T-cells B-cells T-cells B-cells Cmpd (IC50) (IC50) Cmpd(IC50) (IC50) Cmpd (IC50) (IC50) Cmpd (IC50) (IC50)  1 B A 48 B B  95 NDND 143 ND ND  2 B B 49 B B  96 ND ND 144 ND ND  3 B B 50 C C  97 ND ND145 ND ND  4 C C 51 B B  98 A A 146 ND ND  5 C C 52 C C  99 B B 147 NDND  6 B B 53 ND ND 100 B B 148 ND ND  7 B B 54 ND ND 101 A A 149 ND ND 8 B B 55 ND ND 102 B B 150 ND ND  9 B B 56 ND B 103 B A 151 ND ND 10 BC 57 B B 104 A A 152 ND ND 11 C B 58 B B 105 B B 153 ND ND 12 B B 59 C B106 A A 154 ND ND 13 B B 60 B B 107 B B 155 ND ND 14 C B 61 B B 108 B A156 ND ND 15 B B 62 B B 109 B B 157 A A 16 C C 63 B B 110 B A 158 C B 17C C 64 ND ND 111 B B 159 B B 18 C C 65 B B 112 C C 160 ND ND 19 B B 66 CC 113 C C 161 ND ND 20 B B 67 B B 114 C C 162 B B 21 B C 68 B B 115 C C163 A A 22 B B 69 B B 116 C C 164 B B 23 A A 70 C C 117 C C 165 ND ND 24C C 71 C C 118 B B 166 B B 25 B B 72 B B 119 B B 167 ND ND 26 A A 73 C C120 C C 168 B B 27 A A 74 C C 121 ND ND 169 A A 28 B B 75 B B 122 C C170 B B 29 A A 76 A A 123 C C 171 B A 30 C B 77 B B 125 B B 172 C C 31ND ND 78 B B 126 C C 173 C B 32 B A 79 B B 127 C C 174 C B 33 B B 80 B A128 B B 175 C C 34 C B 81 B B 129 B B 176 C C 35 B B 82 B B 130 B C 177ND ND 36 C C 83 B B 131 B B 178 ND ND 37 B B 84 B B 132 B B 179 C C 38 BB 85 ND ND 133 ND ND 180 B C 39 B B 86 C C 134 B B 181 A A 40 C B 87 A A135 ND ND 182 C B 41 B B 88 B B 136 ND ND 183 B B 42 B B 89 A A 137 NDND 184 B B 43 B B 90 B B 138 B B 185 B A 44 B B 91 C C 139 ND ND 186 NDND 45 B B 92 B B 140 ND ND 187 B A 46 B B 93 ND ND 141 ND ND 47 B B 94ND ND 142 ND ND

EXAMPLE 5 Anti-Viral Assays

[0156] The anti-viral efficacy of compounds may be evaluated in variousin vitro and in vivo assays. For example, compounds may be tested in invitro viral replication assays. In vitro assays may employ whole cellsor isolated cellular components. In vivo assays include animal modelsfor viral diseases. Examples of such animal models include, but are notlimited to, rodent models for HBV or HCV infection, the Woodchuck modelfor HBV infection, and chimpanzee model for HCV infection.

[0157] While we have hereinbefore presented a number of embodiments ofthis invention, it is apparent that our basic construction can bealtered to provide other embodiments which utilize the methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the claims appended hereto rather than thespecific embodiments which have been presented hereinbefore by way ofexample.

We claim:
 1. A compounds of formula (A):

wherein: each of R₁ and R₂ is independently selected from hydrogen;—CF₃; —(C₁-C₆)-straight or branched alkyl; —(C₂-C₆)-straight or branchedalkenyl or alkynyl; —(C₁-C₆)-straight or branched alkyl-R₇;—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇ or —R₇; andwherein at least one of R₁ or R₂ is —(C₁-C₆)-straight or branchedalkyl-R₇; —[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇ or —R₇wherein up to 4 hydrogen atoms in any of said alkyl, alkenyl or alkynylare optionally and independently replaced by R₃; and wherein one or bothof R₁ or R₂ are optionally esterified to form a prodrug; or wherein R₁and R₂ are alternatively taken together to form tetrahydrofuranyl,wherein when R₉ is hydrogen, (R)-methyl, (R)-ethyl or (R)-hydroxymethyl,one hydrogen atom in said tetrahydrofuran is replaced by —OR₆ or —R₇,and wherein when R₉ is (S)-methyl, (S)-ethyl or (S)-hydroxymethyl, onehydrogen atom in said tetrahydrofuran is optionally replaced by —OR₆ or—R₇; wherein when R₉ is hydrogen, (R)-methyl, (R)-ethyl or(R)-hydroxymethyl and each of R₁ and R₂ are independently hydrogen,unsubstituted —(C₁-C₆)-straight or branched alkyl, or unsubstituted—(C₂-C₆)-straight or branched alkenyl or alkynyl, then the portion ofthe compound represented by —CH(R₁)R₂ is a C₅-C₁₂ straight or branchedalkyl, alkenyl or alkynyl; each R₃ is independently selected from halo,CN, —OR₄, or —N(R₅)₂; R₄ is selected from hydrogen, —(C₁-C₆)-straight orbranched alkyl, —(C₂-C₆)-straight or branched alkenyl or alkynyl,—[(C₁-C₆)-straight or branched alkyl]-R₇, —[(C₂-C₆)-straight or branchedalkenyl or alkynyl]-R₇, —C(O)—[(C₁-C₆)-straight or branched alkyl],—C(O)—[(C₂-C₆)-straight or branched alkenyl or alkynyl],—C(O)—[(C₁-C₆)-straight or branched alkyl]-N(R₈)₂,—C(O)—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-N(R₈)₂,—P(O)(OR₈)₂, —P(O)(OR₈)(R₈), —C(O)—R₇, —S(O)₂N(R₅)₂, —[(C₁-C₆)-straightor branched alkyl]-CN, or —[(C₂-C₆)-straight or branched alkenyl oralkynyl]-CN; each R₅ is independently selected from hydrogen,—(C₁-C₆)-straight or branched alkyl, —(C₂-C₆)-straight or branchedalkenyl or alkynyl, —[(C₁-C₆)-straight or branched alkyl]-R₇,—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-R₇,—[(C₁-C₆)-straight alkyl]-CN, —[(C₂-C6)-straight or branched alkenyl oralkynyl]-CN, —[(C₁-C₆)-straight or branched alkyl]-OR₄,—[(C₂-C₆)-straight or branched alkenyl or alkynyl]-OR₄,—C(O)—(C₃-C₆)-straight or branched alkyl, —C(O)—[(C₂-C₆)-straight orbranched alkenyl or alkynyl], —C(O)—R₇, —C(O)—R₇,—C(O)O—(C₁-C₆)-straight or branched alkyl, —C(O)O—[(C₂-C₆)-straight orbranched alkenyl or alkynyl], —S(O)₂—(C₁-C₆)-straight or branched alkyl,or —S(O)₂—R₇; or two R₅ moieties, when bound to the same nitrogen atom,are taken together with said nitrogen atom to form a 3 to 7-memberedheterocyclic ring, wherein said heterocyclic ring optionally contains 1to 3 additional heteroatoms independently selected from N, O, S, S(O) orS(O)₂; R₆ is selected from —C(O)—CH₃, —CH₂—C(O)—OH, —CH₂—C(O)—O-tBu,—CH₂—CN, or —CH₂-C≡CH; each R₇ is a monocyclic or bicyclic ring systemwherein in said ring system: i. each ring comprises 3 to 7 ring atomsindependently selected from C, N, O or S; ii. no more than 4 ring atomsare selected from N, O or S; iii. any CH₂ is optionally replaced withC(O); iv. any S is optionally replaced with S(O) or S(O)₂; each R₈ isindependently selected from hydrogen or —[C₁-C₄]-straight or branchedalkyl; wherein in any ring system in said compound up to 3 hydrogenatoms bound to the ring atoms are optionally and independently replacedwith halo, hydroxy, nitro, cyano, amino, (C₁-C₄)-straight or branchedalkyl; O—(C₁-C₄)-straight or branched alkyl, (C₂-C₄)-straight orbranched alkenyl or alkynyl, or O—(C₂-C₄)-straight or branched alkenylor alkynyl; and wherein any ring system is optionally benzofused; R₉ isselected from hydrogen, (R)-methyl, (s)-methyl, (R)-ethyl, (S)-ethyl,(R)-hydroxymethyl or (S)-hydroxymethyl; R₁₀ is selected from —C≡N or5-oxazolyl; and R₁₁ is selected from halo, —O—(C₁-C₃) straight alkyl, or—O—(C₂-C₃) straight alkenyl or alkynyl.
 2. The compound according toclaim 1, wherein said compound has the formula (I):

wherein R₁ and R₂ are as defined in claim
 1. 3. The compound accordingto claim 1, wherein said compound has the formula (IA):

wherein R₉ is selected from (R)-methyl, (S)-methyl, (R)-ethyl,(S)-ethyl, (R)-hydroxymethyl or (S)-hydroxymethyl; and R₁ and R₂ are asdefined in claim
 1. 4. The compound according to claim 3, wherein R₉ isselected from (S)-methyl, (S)-ethyl, or (S)-hydroxymethyl methyl.
 5. Thecompound according to claim 4, wherein R₉ is (S)-methyl.
 6. The compoundaccording to claim 3, wherein R₁₁ is selected from O-methyl, O-ethyl orO-isopropyl.
 7. The compound according to claim 1, wherein: at least oneof R₁ or R₂ is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, n-pentyl, phenyl, pyridyl, —CH₂OCH₃,—CH₂CN, —CH₂OCH₂CH₂CN, —CH₂C(CH₃)₂CH₂CH₂CN, —CH₂C(CH₂CH₃)₂CH₂CH₂CN,—CH₂CH₂CN, —CH₂N(CH₂CH₂CN)₂, —CH₂N(CH₃)CH₂CH₂CN, —CH(NH₂)CH₂CN, —CH₂Cl,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂OC(O)CH₃,—CH₂CH₂OC(O)CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂N(CH₂CH₃)₂,—CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂N⁺(CH₃)₃,—CH₂OCH₂CH(CH₃)₂, —CH₂CH₂N(CH₃)C(O)OC(CH₃)₃, —CH₂N(CH₂CH₂CN)CH₂CH(CH₃)₂, —CH(CH₂CN)N(CH₃)₂, —CH₂CH(CH₂CN)NHC(O)OC(CH₃)₃,

wherein n is 0 or
 1. 8. The compound according to claim 2, wherein R₁and R₂ are taken together to form a 3-tetrahydrofuranyl moiety that issubstituted at the 5 position by —OR₆.
 9. The compound according toclaim 3, wherein one of R₁ or R₂ is selected from hydrogen, ethyl orphenyl; and the other of R₁ or R₂ is selected from —CH₂OH, —CH₂CN,—CH₂CH₂CN or CH₂N(CH₂CH₃)₂; or wherein R₁ and R₂ are taken together toform a 3-tetrahydrofuranyl moiety.
 10. The compound according to claim1, wherein said compound is selected from any one of compounds 1 to 187in Table
 1. 11. The compound according to claim 10, wherein saidcompound is selected from any one of compounds 1, 23, 26, 27, 29, 32,76, 80, 87, 89, 98, 101, 103, 104, 106, 108, 110, 157, 163, 169, 171,181, 185, 186 or 187 in Table
 1. 12. A composition comprising a compoundaccording to claim 1 in an amount effective to inhibit IMPDH and apharmaceutically acceptable carrier, adjuvant or vehicle.
 13. Thecomposition according to claim 12, further comprising of this inventioncomprise a compound an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,anti-inflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation compound.
 14. A method of treating orpreventing an IMPDH-mediated disease or condition in a mammal comprisingthe step of administrating to said mammal a composition according toclaim 12 or
 13. 15. The method according to claim 14, wherein saidIMPDH-mediated disease or condition is selected from transplantrejection, graft versus host disease, an autoimmune disease.
 16. Themethod according to claim 14, wherein said mammal is administered anadditional immunosuppressant in a separate dosage form or as part ofsaid composition.
 17. A method for inhibiting viral replication in amammal comprising the step of administering to said mammal a compositionaccording to claim 12 or
 13. 18. The method according to claim 17,wherein 7said mammal is suffering from a viral infection caused by avirus selected from orthomyxovirus, paramyxovirus, herpesvirus,retrovirus, flavivirus, pestivirus, hepatotrophic virus, bunyavirus,Hantaan virus, Caraparu virus, human papilloma virus, encephalitisvirus, arena virus, reovirus, vesicular stomatitis virus, rhinovirus,enterovirus, Lassa fever virus, togavirus, poxvirus, adenovirus,rubiola, or rubella is inhibited.
 19. The method according to claim 17,wherein said mammal is administered an additional anti-viral agent in aseparate dosage form or as part of said composition.
 20. A method forinhibiting vascular cellular hyperproliferation in a mammal comprisingthe step of administrating to said mammal a composition according toclaim 12 or
 13. 21. The method according to claim 20, wherein saidmethod is useful in treating or preventing restenosis, stenosis,artherosclerosis or other hyperproliferative vascular disease.
 22. Themethod according to claim 20, wherein said mammal is administered anadditional anti-vascular hyperproliferative agent in a separate dosageform or as part of said composition.
 23. A method for inhibiting tumorsand cancer in a mammal comprising the step of administrating to saidmammal a composition according to claim 12 or
 13. 24. The methodaccording to claim 23, wherein said method is useful to treat or preventlymphoma, leukemia and other forms of cancer.
 25. The method accordingto claim 24, wherein said mammal is administered an additionalanti-tumor or anti-cancer agent in a separate dosage form or as part ofsaid composition.
 26. A method for inhibiting inflammation or aninflammatory disease in a mammal comprising the step of administering tosaid mammal a composition according to claim 12 or
 13. 27. The methodaccording to claim 26, wherein said method is useful for treating orpreventing osteoarthritis, acute pancreatitis, chronic pancreatitis,asthma or adult respiratory distress syndrome.
 28. The method accordingto claim 27, wherein said mammal is administered an additionalanti-inflammatory agent in a separate dosage form or as part of saidcomposition.